High‐throughput DNA sequencing technology provides base‐level and statistically rich information about the genomic content of a sample. In the contexts of cancer research and precision oncology, thousands of genomes from paired tumor and matched normal samples are profiled and processed to determine somatic copy‐number changes and single‐nucleotide variations. Higher‐order informative analyses, in the form of allele‐specific copy‐number assessments or subclonality quantification, require reliable estimates of tumor DNA ploidy and tumor cellularity. CLONETv2 provides a complete set of functions to process matched normal and tumor pairs using patient‐specific genotype data, is independent of low‐level tools (e.g., aligner, segmentation algorithm, mutation caller) and offers high‐level functions to compute allele‐specific copy number from segmented data and to identify subclonal population in the input sample. CLONETv2 is applicable to whole‐genome, whole‐exome and targeted sequencing data generated either from tissue or from liquid biopsy samples. © 2019 The Authors.